As the most important key enzyme in intracellular tricarboxylic acid cycle, IDH (full name: isocitrate dehydrogenase) can catalyze oxidative decarboxylation of isocitric acid to 2-oxoglutarate (i.e., α-ketoglutaric acid). Researches have shown that many tumors (such as, glioma, sarcoma, and acute myelocytic leukemia) have an IDH mutation at arginine residue in a catalytic center (IDH1/R132H, IDH2/R140Q, and IDH2/R172K). The mutated IDH acquires a new ability to catalyze the conversion of α-ketoglutaric acid (α-KG) to 2-hydroxyglutaric acid (2-HG). Researches have shown that the structure of α-ketoglutaric acid is similar to that of 2-hydroxyglutaric acid, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes, and resulting in a high methylation of chromatin. Such supermethylation is considered to interfere with a normal cell differentiation, and lead to an excessive proliferation of immature cells, thereby resulting in cancers.
In 2013, Agios Pharmaceuticals reported an IDH2/R140Q inhibitor AGI-6780 (Science. 2013, 340, 622-626) and an IDH1/R132H inhibitor AGI-5198 (Science. 2013, 340, 626-630), and WO2015017821 disclosed another IDH2/R140Q inhibitor AG-221. AGI-6780 and AGI-5198 can inhibit the generation of 2-HG in cells carrying the most common IDH2 mutant and the most common IDH1 mutant, respectively. These molecules not only inhibit the generation of 2-HG, but also induce the differentiation of abnormally proliferated human cancer cells in a culture. The treatment of leukemia cells carrying the IDH2 mutant with AGI-6780, and the treatment of glioma cells carrying the IDH1 mutant with AGI-5198 both result in an enhanced expression of mature markers in these cells. Moreover, researchers have found that AGI-5198 can inhibit the growth rate of the glioma cells either by the treatment of cell cultures with AGI-5198 or by oral administration of AGI-5198 to mice with a transplanted tumor.